chemical characterization/risk assessment approach for

Chemical Characterization/Risk Assessment Approach for

Biocompatibility Assessment

Current Successes and Future Challenges

Ron Brown

US FDA (retired)

Risk Science Consortium

Disclaimer

The information in this presentation does not represent the official position

of the US FDA.

Nelson Labs Open House - The Future of Chemical Characterization 2

Biocompatibility assessment of devices takes into account

multiple biological

endpoints (e.g., cytotoxicity,

irritation, sensitization)


Approaches for biocompatibility evaluation of medical devices

4

Biocompatibility testing of extracts or intact device

Chemical characterization/toxicological

risk assessment

The US FDA is seeing an increasing number of submissions

that use the chemical characterization/risk assessment

approach to evaluate some endpoints in a biocompatibility

evaluation strategy.

Nelson Labs Open House - The Future of Chemical Characterization

Approaches for the

Biological Safety

Evaluation of Medical Devices

Current Successes

FDA Biocompatibility Guidance Document

Defines when the chemical characterization/risk assessment can be used in a biocompatibility assessment.

Incorporates a number of cutting edge concepts (use of SAR modeling, TTC).

Underscores the acceptance by FDA of qualified alternatives to biocompatibility testing in animals.


Section III. C. Considering Available Information to Identify and Mitigate Risks

• As an alternative to conducting systemic toxicity, genotoxicity, carcinogenicity, or developmental/reprotox tests (not other endpoints).

Section VII. Chemical Assessment

• When the device contains compounds known to be toxic.

• To evaluate the safety of absorbable/degradable or novel materials.

• To explain positive results in biocompatibility tests.

6

When is the Chemical

Characterization/Risk Assessment

Approach Accepted (or

Requested) by the US FDA?

Nelson Labs Open House - The Future of Chemical Characterization

FDA Biocompatibility Guidance (2016)

Current Successes

Chemical Characterization/Risk Assessment Approach

Advantages

May be more cost efficient,especially when used as analternative to lengthy andcostly bioassays.

May reduce preclinicalevaluation time for newdevices and reduce animaluse.

Can be used to quicklyassess potentialtoxicological risk associatedwith design, material,supplier, or processingchange.

Challenges

Chemical characterization isnot a trivial process,requires considerableexpertise.

May require toxicity data (ordefault approach) forhundreds of compounds

Requires expertise and anew skill set beyond typicalbiocompatibilityassessment.

7Nelson Labs Open House - The Future of Chemical Characterization

Current Successes

Revision of ISO 10993-17 and -18


ISO 10993-17 and -18 ISO 10993-17

Both standards are currently undergoing revision

Current Successes

TTC and AET

Chemistry Toxicity


Implementation of the chemical

characterization/risk assessment

approach would not be possible

without the use of the TTC concept

Allowed us to develop

an analytical threshold

(AET) for the

identification and

quantification of

toxicologically relevant

compounds.

Allowed us to develop

science-based default TI

values to use when

toxicity data do not

exist to derive the TI.

Future Challenges

Chemistry/Exposure

Address variability and uncertainty in chemical characterization steps.

Provide clinically relevant exposure estimates.

Toxicity

Develop consensus TIs

Identify best practices for the use of in silico models

Continue efforts to qualify alternative methods.


Additional guidance and training in this area is needed to

reduce regulatory uncertainty and to ensure that the

regulated industry is preparing high-quality chemical

analyses and toxicological risk assessments.

Future Challenge

Address uncertainty and variability in chemical characterization

From a toxicological perspective, much of the uncertainty in the chemical characterization step is associated with the large number of structurally unidentified compounds in the extract.

This makes the toxicological risk assessment step difficult or results in the use of conservative default assumptions.


Future challenge

Address uncertainty and variability in chemical characterization

Variation in Chemical Characterization Results from Four Test Laboratories

Monica Posgai, Johnson & Johnson, 2018 Society of Toxicology Annual Meeting

For example, the reported number of elements in thepolyurethane water extract ranged between 0 and 12 for thefour labs. For the polyisoprene isopropyl alcohol extract, thereported number of gas chromatography-mass spectrometrycompounds ranged between 12 and 156 for the four labs.

This study into inter-laboratory comparisons revealedconsiderable quantitative and qualitative differences amongchemical characterization results, which can potentiallyimpact the outcome of a risk assessment.


Future Challenge

Provide clinically relevant estimates of exposure

Problem

Data are often not available on the rate at which leachable compounds are released from devices. As a default, the assumption is made that either:

The total amount of each compound in the device is released in one day (typically results in overestimate of daily dose), or

The total amount of each compound is released linearly over the lifetime of the device (typically results in underestimate of daily dose).


Future Challenge

Provide clinically relevant estimates of exposure

Proposed solutions

Simple approach: Need more clinically relevant default assumptions for the rate at which leachable compounds are released from different types of polymers

Use computational approaches to predict release kinetics:

https://www.fda.gov/MedicalDevices/ScienceandResearch/ResearchPrograms/ucm477410.htm


https://www.fda.gov/MedicalDevices/ScienceandResearch/ResearchPrograms/ucm477410.htm

Use of

computational

models to

predict patient

exposure to

additives in

polymers and

metals (e.g.,

nickel)

released from

metallic

implants


Future Challenges

Chemistry/Exposure



Toxicity









Future Challenge

Harmonize requirements for toxicological risk assessment

Problem

The quality of toxicological risk assessments provided in regulatory dossiers is highly variable.

Regulatory agencies do not uniformly assess the adequacy of risk assessments provided in regulatory submissions.

Proposed solutions

Revise and publish ISO 10993-17 and -18.

Provide training on how to prepare toxicological risk assessments that will be accepted by regulatory agencies and third party assessors.


Future Challenge

Harmonize requirements for toxicological risk assessment

Problem: Variability in Tolerable Intake values for the same compound

TI values for a given compound can be derived using different toxicity data sets and Uncertainty Factors.

Proposed solution: Develop a database of consensus TI values for commonly encountered E&L compounds

Promote uniformity in decision-making,

Increase confidence in derived values,

Result in more efficient use of resources, and

Reduce time/cost needed to prepare each risk assessment.


Future challenge

Regulatory acceptance of in silico predictions of toxicity

Problem

Toxicity data are not available for many compounds released from device materials.

Solutions

Use TTC as a default TI

Use computational models (e.g., structure-activity relationship models) to select an appropriate TTC

Use computational models (e.g., Read Across) identify NOAEL values to serve as basis for the TIs.


Proposed Approaches Outlined in ISO 10993-17 (draft revision) to Derive

Default TI Values in the Absence of Compound-Specific Toxicity Data

Slide used with permission of Dr. Sherry Parker, Fresenius Medical CareNelson Labs Open House - The Future of Chemical Characterization 20

Role of SAR Modeling when the Chemical Characterization/Risk Assessment Approach is Used

From CDRH Biocompatibility Guidance:

In the absence of experimentally derived carcinogenicity information, structure activity relationship (SAR) modeling

for these materials may be needed regardless of the duration of contact, to better understand the carcinogenicity potential for these materials.

SAR models are typically used to determine which TTC value is appropriate to use as a default TI value for the compound:

Possible carcinogen: Use cancer-based TTC value

Not likely to be carcinogen: Use noncancer TTC value


Use of QSAR models and Read Across approaches to predict toxicity

for data-poor compounds may not be universally accepted by all

regulatory agencies and Notified Bodies

Future challenge

Regulatory acceptance of in silico predictions of toxicity

Proposed Solutions

Provide initial guidance in ISO 10993-17 on how to use in silico models to predict toxicity.

Develop best practices for the use of computational approaches for the biological safety assessment of medical devices.


Future Challenge

Consider a hybrid in silico-in vitro approach to predict toxicity

Proposal: Consider a hybrid approach that takes into account in silico prediction of genotoxicity/carcinogenicity of extractables and in vitro genotoxicity testing of an extract of the device.

What should we do when the results of the in silico prediction and in vitro genotoxicity assay of the extract don’t agree?

From ICH M7: An appropriately conducted negative bacterial mutagenicity assay (Note 2) would overrule any structure-based

concern, and no further genotoxicity assessments would be recommended (Note 1). These impurities should be considered non-

mutagenic (Class 5 in Table 1).


In Vitro Genotoxicity

POS NEG

In Silico

Prediction

POS POS NEG

NEG POS NEG

Future Challenge

Adopt hybrid approach to predict genotoxicity/carcinogenicity

Proposed approach may result in a small amount of additional testing (e.g., Ames test of an extract of the device), but would:

Provide increased confidence in genotoxicity/carcinogenicity predictions,

Account for potential interactive effects among compounds extracted from device, and

Represent a practical way to deal with Margin of Safety values < 1 when conservative cancer-based TTC values are used as the basis for the default TI.

This approach does not necessarily represent current FDA policy.


FDA Biocompatibility Guidance (2016)

“…FDA agrees with the ISO 10993-1:2009 revision focus on minimizing the “number and exposure of test animals by giving preference to chemical constituent testing and in vitro models, in situations where these methods yield equally relevant information to that obtained from in vivo

models.”

https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm348890.pdf25

Future

Challenges

Regulatory

Acceptance

of

Alternative

Approaches

https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm348890.pdf

FDA Predictive Toxicology Roadmap (2018)

26

Future

Challenges

Regulatory

Acceptance

of

Alternative

Approaches

• Foster the

development and

evaluation of

emerging

toxicological

methods and new

technologies, and

• Incorporate these

methods and

technologies into

regulatory review,

as applicable.

https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RegulatoryScience/UCM587831.pdf

Future ChallengesMethods to Validate In Vitro Methods for the Biocompatibility

Assessment of Device Extracts


Staff from Nelson Labs have played an important

role in the validation of this method


https://www.fda.gov/medicaldevices/scienceandresearch/medicaldevicedevelopmenttoolsmddt/Nelson Labs Open House - The Future of Chemical Characterization 29

Summary

Current Successes

1. Chemical characterization/risk assessment approach isbecoming increasingly accepted by regulatory agencies (e.g.,US FDA).

2. Revision of the ISO 10993-17 and -18 standards will addressmany of the outstanding issues.

3. Practical application of this method is possible throughacceptance of TTC concept and use of TTC to establish AETand default TI values.


Do you think the Chemical Characterization/Risk

Assessment approach has been successful as a means to

improve the efficiency of the biocompatibility

evaluation process?

Summary

Future Challenges

Chemistry/Exposure



Toxicity









What challenges do you see associated with the

successful implementation of the Chemical

Characterization/Risk Assessment approach?

Implications for CROs and clients

Since many regulatory agencies and Notified Bodies arecurrently accepting the chemical characterization/riskassessment approach as an alternative tobiocompatibility testing for some endpoints (e.g.,systemic tox), this method provides another tool todevelop a biocompatibility evaluation strategy for yourdevice. In some cases, this approach may result in lowertesting costs and reduced testing time.

However, enhanced capabilities are needed tosuccessfully implement this approach. Successfulcompletion of the chemical analysis and preparation ofthe toxicological risk assessment will reduce the timeneeded for regulatory review of preclinical data insubmitted dossiers.


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